Smad6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway, which is crucial for regulating early embryonic development and tissue homeostasis [1,2,3].

SMAD6-deficiency has been linked to three human congenital conditions: congenital heart diseases, craniosynostosis, and radioulnar synostosis [1]. Rare heterozygous loss-of-function variants in SMAD6 increase the risk of these disorders, and even identical nucleotide changes can lead to different phenotypes without a clear genotype-phenotype correlation [1]. Homozygous SMAD6 variants have also been found in patients with craniosynostosis and radioulnar synostosis, expanding the phenotypic spectrum [3]. In addition, some rare pathogenic SMAD6 variants can activate the BMP signaling pathway through deamidation, revealing a new pathogenic mechanism [2]. SMAD6 is also frequently mutated in nonsyndromic radioulnar synostosis [4].

In summary, Smad6 is an important negative regulator of the BMP signalling pathway. Research on SMAD6-related genetic variants in humans has provided insights into its role in congenital heart diseases, craniosynostosis, and radioulnar synostosis, helping to understand the pathogenesis of these diseases and potentially improve molecular diagnosis and therapeutic strategies [1,2,3,4].

References:

1. Luyckx, Ilse, Verstraeten, Aline, Goumans, Marie-José, Loeys, Bart. 2022. SMAD6-deficiency in human genetic disorders. In NPJ genomic medicine, 7, 68. doi:10.1038/s41525-022-00338-5. https://pubmed.ncbi.nlm.nih.gov/36414630/

2. Li, Ling, Lu, Lei, Xiao, Ziqi, Wang, Weimin, Wang, Hongyan. 2024. Deamidation enables pathogenic SMAD6 variants to activate the BMP signaling pathway. In Science China. Life sciences, 67, 1915-1927. doi:10.1007/s11427-023-2532-5. https://pubmed.ncbi.nlm.nih.gov/38913236/

3. Luyckx, Ilse, Walton, Isaac Scott, Boeckx, Nele, Wilkie, Andrew O M, Loeys, Bart. 2024. Homozygous SMAD6 variants in two unrelated patients with craniosynostosis and radioulnar synostosis. In Journal of medical genetics, 61, 363-368. doi:10.1136/jmg-2023-109151. https://pubmed.ncbi.nlm.nih.gov/38290823/

4. Yang, Yongjia, Zheng, Yu, Li, Wangming, Zhu, Guanghui, Zhu, Yimin. 2019. SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis. In Genetics in medicine : official journal of the American College of Medical Genetics, 21, 2577-2585. doi:10.1038/s41436-019-0552-8. https://pubmed.ncbi.nlm.nih.gov/31138930/